The focus of this research proposal is the mechanism of tumor induction by the v-abl oncogene. Experiments with monoclonal populations of transformed cells recovered from mice infected with helper virus-free Abelson murine leukemia virus have indicated that expression of the v-abl oncogene, though necessary, is not sufficient for tumor induction in mice. Using transformed cells recovered from such preleukemic mice and immunoglobulin gene rearrangements, the target cell for tumorigenesis will be identi- fied and the process of clonal selection during tumor progression characterized. Using self-inactivating A-MuLV variants that undergo only a single cycle of replication, the role of helper virus in mice resistant to tumorigenesis by helper virus-free A- MuLV but susceptible to tumor induction by helper virus-free A-MuLV and helper virus will be determined. Cellular genes that potentiate A-MuLV tumorigenesis and may be targets for insertional mutagenesis by helper virus will be identified, and their role in A-MuLV tumor induction examined. The activities of helper virus- free A-MuLV variants that contain substituted LTRs or partial deletions in the v-abl oncogene will be analyzed by in vitro transformation of lymphoid cells and in vivo tumorigenesis in susceptible and resistant mice. Such experiments will provide insights into the genetic basis of susceptibility to tumor formation. The consequences of v-abl oncogene expression will be analyzed in non-B cell compartments of the hematopoietic lineage in order to more precisely define its oncogenic potential. Bone marrow reconstitution experiments with cells infected with retroviral vectors encoding v-abl will provide such a system. A transformation assay using A-MuLV infection of primary fetal thymocytes will be further characterized.